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Background: An alarming increase in infections due to penicillin non-susceptible pneumococci (PNSP) has been documented in nearly all countries. Increasingly, PNSP are also resistant to other antibiotics, and a growing number of clinical failures following the use of these agents have been reported. Aims: To determine the resistance pattern of pneumococcal isolates from patients with invasive pneumococcal infection in North West Nigeria. Materials and Methods: In a cross-sectional study clinical specimens were obtained from patients with community acquired pneumonia (CAP), meningitis and bacteraemia over a 2 year period. Pneumococcus strains were identified. Isolates were tested against a panel of antibiotics using E-test strips, and interpreted according to the CLSI criteria. 0.06 ΅g/ml was used as break point for penicillin. Analysis was carried out using descriptive statistics; relationships determined using chi-squared or Fisher′s exact tests, with P < 0.05 regarded as significant. Results: Total number of isolates was 132. Twenty-two (16.7%) of the isolates were fully sensitive to penicillin while 73 (55.3%) and 37 (28.0%) were intermediately and fully resistant, respectively. One hundred and twenty-seven (96.2%) of the isolates were fully resistant to trimethoprim-sulphamethoxazole. Eleven (8.5%) were fully resistant to amoxicillin and 104 (78.8%) and 17 (12.9%) were intermediately resistant and fully susceptible. One hundred and six (80.3%) of the isolates were fully susceptible to chloramphenicol. Resistance to penicillin was shown to infer resistance to other antibiotics. Conclusions: Pneumococcal resistance is common in North West Nigeria. Ceftriaxone retains excellent activity against most of the invasive isolate, while trimethoprim-sulphamethoxazole is almost uniformly resistant.